The incidence of obesity and related metabolic disorders is currently increasing at an alarming rate in modern society. Therefore, the development of effective antiobesity therapies represents a high priority area for the research-based pharmaceutical industry. The search for lipid mediators that control metabolism is now one of the major goals of obesity research. The fatty acid ethanolamides (FAEs) are a family of bioactive lipid mediators that play multiple roles in living organisms, including plants and vertebrates. The present review focuses on the naturally occurring FAE oleoylethanolamide (OEA), a mediator of satiety that exerts anorectic effects mainly through peripheral mechanisms. This property is essential to avoid central effects and minimize the risk of adverse reactions that may limit its use. In mammals, OEA has been described as a mediator of lipid metabolism, insulin secretion, energy expenditure and gastrointestinal motility based upon its mechanism of action and its main target receptors: the peroxisome proliferator activated-receptor alpha (PPAR-α) and the orphan receptor GPR119. Additional anti-inflammatory and neuroprotective actions of OEA have been suggested. In the present article, we review the roles of OEA and drugs developed from this acylethanolamide using a structure–activity relationship approach.